A practical approach to the diagnosis of type 1 diabetes: An Indian perspective Suganthi K, Lalvani N, Jevalikar GS, Sarda A, Unnikrishnan AG,

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A practical approach to the diagnosis of type 1 diabetes: An Indian perspective

Kumaran Suganthi¹, Nupur Lalvani², Ganesh S Jevalikar³, Archana Sarda⁴, Ambika G Unnikrishnan¹
¹ Internal Medicine, Chellaram Diabetes Institute, Pune, Maharashtra, India
² Blue Circle Diabetes Foundation, Pune, Maharashtra, India
³ Peadiatric Endocrinology, Max Super speciality Hospital, New Delhi, India
⁴ Sarda Center for Diabetes and Self Care, Aurangabad, Maharashtra, India

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Date of Submission	13-Aug-2022
Date of Decision	12-Sep-2022
Date of Acceptance	20-Sep-2022
Date of Web Publication	17-Feb-2023

Abstract

There are more than 1 million people living with type 1 diabetes worldwide. People with classical type 1 diabetes are often, though not always young and require insulin therapy life long without which they are at risk of ketoacidosis. The proper and early diagnosis of type 1 diabetes is critical because of therapeutic implications and the prevention of diabetes-related complications. As the incidence of type 1 diabetes is increasing in India, and given unique socioeconomic challenges in the diagnosis and management of type 1 diabetes in India, it is important to approach the diagnosis from an Indian perspective. In this article, we discuss the practical aspect of clinical presentation and diagnosis of type 1 diabetes.

Keywords: C-peptide, islet cell autoantibodies ketoacidosis, monogenic diabetes, type 1 diabetes

How to cite this URL:
Suganthi K, Lalvani N, Jevalikar GS, Sarda A, Unnikrishnan AG. A practical approach to the diagnosis of type 1 diabetes: An Indian perspective. Chron Diabetes Res Pract [Epub ahead of print] [cited 2023 Jun 2]. Available from: https://cdrpj.org//preprintarticle.asp?id=369951

Introduction

The incidence of type 1 diabetes mellitus (T1DM) is increasing. There are more than 1.2 million people living with T1DM as per International Diabetes Federation (IDF).^[1] A recent study found the incidence of T1DM in India is 4.9 cases/100,000/year which is much lower than the incidence of 21.2 cases/100,000/year, observed in the SEARCH registry of the USA.^[2] A systematic review and meta-analysis study showed that the annual incidence of T1DM in Asia was 15/100,000 people and the prevalence was 9.5% in the world.^[3] As viral infection may increase the risk of TIDM, COVID-19 pandemic has significantly increased the risk of incidence of global T1DM in the pediatric age group by 9.5% in 2020, when compared to pre-COVID pandemic levels.^[4] The classic presentation of abrupt onset, requiring hospitalization with ketoacidosis precipitated by an acute illness and a history of few weeks of polyuria, polydipsia, and weight loss is becoming less common.^[5] Majority of patients with T1DM however, still present with classic symptoms of polyuria, polydipsia, and weight loss. Timely diagnosis of T1DM can prevent diabetic ketoacidosis (DKA), need of hospitalization and may be potentially lifesaving. A correct diagnosis can also help chart out the natural history and help in appropriate therapy. This manuscript provides a protocol for correctly identifying T1DM, especially in the Indian Scenario. This article is generally consistent with the recommendations of the International Society for Pediatric and Adolescent Diabetes clinical practice consensus 2018 guidelines including checking for diabetes-related autoantibodies when the diagnosis of TIDM is unclear.^[6]

Epidemiology

About 5%–10% of people with diabetes have T1DM. The incidence of T1DM is increasing by about 3%–5% cases per year.^[7] In the absence of large population data, the exact prevalence of T1DM in India is not known. However, regional studies from Karnataka, Chennai, and Karnal (Haryana) have documented a prevalence of 17.93, 3.2, and 10.2 per 100,000, respectively.^[8],[9],[10]

Definition

Diabetes mellitus (DM) is a chronic progressive metabolic disease resulting from insulin deficiency, insulin resistance, or both. Type 2 DM (T2DM), the most common form, constitutes about 90%–95% of DM cases. It results from insulin resistance eventually leading to insulin deficiency. T1DM accounts for about 5%–10% of diabetes and results from failure of pancreatic beta cells to produce insulin and this could be either due to autoimmune or idiopathic causes.^[6],[11]

T1DM is further classified into type 1A and 1B based on the presence or absence of evidence of autoimmunity. Distinguishing these two types is significant as people with type 1A diabetes need testing for coexisting endocrine autoimmunity.^{[12],[13],[14]} Moreover, the distinction is of research interest given that several immunotherapies are being experimentally considered for type 1A diabetes. Latent autoimmune diabetes of Adult (LADA) is a slowly progressive form of type 1 diabetes. LADA is not initially insulin-requiring, but insulin deficiency soon sets in.

Clinical Features

The typical presentation of T1DM is that of a lean child, presenting with acute or subacute onset of the classical symptom triad of polyuria, polydipsia, and weight loss. The weight loss is present despite normal or more than normal appetite. Delays in diagnosis are common, leading to the presence of ketosis or ketoacidosis in nearly half of the cases at the time of the diagnosis.^[13] The hyperglycemia is usually marked and in majority of cases, there is no family history of diabetes. The presence of secondary nocturnal enuresis, recurrent skin and subcutaneous infections, and genital infections like candidiasis may be other presentations. Not all patients with type 1 diabetes present with classical features.

In addition, DKA can present in an emergency department with acute abdomen (sometimes misdiagnosed as surgical abdomen), respiratory distress (misdiagnosed as asthma or pneumonia), and altered sensorium (misdiagnosed as meningitis or encephalopathy). It is important to check bedside blood glucose in these presentations.

The majority of cases of diabetes in the young, with onset <20 years (89%) turn out to have type 1 diabetes.^[14] With increase in childhood obesity over the past couple of decades, there has been increase in the incidence of childhood T2DM. In a study from teaching institutes from India, 6% of patients with diabetes onset below 20 years of age had T2DM.^[14] It is usually seen in children older than 10 years of age with the background of obesity and family history of T2DM (in more than 90% of cases). Features of insulin resistance such as acanthosis, skin tags, and polycystic ovary syndrome can be clues to T2DM. None of the clinical features discussed above are exclusively diagnostic of a particular diabetes type. For example, with background rise of childhood obesity, a proportion of children with T1DM can be overweight or obese at the time of diagnosis. Children with T2DM tend to be more symptomatic than their adult counterparts and rarely can even present with DKA. This highlights the importance of appropriate investigations and clinical judgment.

Challenges in Diagnosing Type 1 Diabetes

The diagnosis of type 1 diabetes is not always straightforward. Adults with new-onset type 1 diabetes present with a short duration of about 1–4 weeks of illness or alternatively may present with a more slowly evolving process when it may be misdiagnosed as T2DM. Monogenic diabetes which occurs in young adults <25 years of age, may also be mistaken for T1DM. In older adults with pancreatic cancer, weight loss and diabetes may be the primary presenting symptoms and this represents a secondary form of new-onset diabetes that is distinct from type 1 and type 2 diabetes as well as the other subtypes.^[15] However, this sudden onset of diabetes mimics presentation of type 1 diabetes in the elderly who are often lean and may have undergone weight loss due to the underlying pancreatic malignancy. New onset diabetes in adults with either normal or low Body Mass Index (BMI) initially responding well to oral antidiabetic medications, progressing rapidly within 1–2 years of diagnosis, resulting in insulin requirement raises the possibility of LADA. This diagnosis of LADA can then be supported by islet antibody testing (see later). Indeed, if the diagnostic type of diabetes is unclear, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) guidelines are excellent sources of information for further management.

An emerging and new issue is the presentation of hyperglycemia and DKA due to profuse insulin deficiency in individuals treated with immune checkpoint inhibitors such as pemprolizumab (programmed cell death receptor 1 inhibitors), avelumab (programmed cell death ligand 1 inhibitor), and ipilimumab (cytotoxic T-lymphocyte associated protein 4 inhibitors).^[16] Furthermore, infection with coxsackie virus B and other enteroviruses causing autoimmune beta cell destruction resulting in the clinical manifestation of insulin-dependent DM, is another conundrum as the study reports of these are accompanied by equivocal evidence.^[17],[18] Recently, studies have also shown that severe acute respiratory syndrome corona virus-2 infection might lead to type 1 or type 2 diabetes through complex and differing mechanisms.^[19] Atypical diabetes is another form of diabetes which may initially mimic type 1 diabetes as it presents with ketoacidosis. But eventually, beta cell function recovers and insulin independence can be achieved in the long term. Another associated disease is ketosis-prone type 2 diabetes, which behaves like type 2 diabetes, but subjects are prone to repeated DKA.^[20] Thus, it is important for clinicians to be aware of these situations.

Diagnosis

The first step is to diagnose diabetes and then differentiate the type depending on clinical features and laboratory data.

As per the ADA, the diagnosis of diabetes includes the following four criteria: the fasting plasma glucose value of ≥126 mg/dl, after an overnight fast of about 8 h (repeated to confirm at least 24 h later), postprandial value of ≥200 mg/dl (repeated to confirm at least 24 h later) or single random plasma glucose value of 200 mg/dl or more, with classical symptoms of hyperglycemia such as polyuria, polydipsia, and weight loss or glycosylated hemoglobin (HbA1c) value of ≥6.5%. In most cases with T1DM, random glucose values are high enough to make a diagnosis in the presence of classic symptoms.

An oral glucose tolerance test (OGTT) is unnecessary and can potentially worsen hyperglycemia. Although unnecessary in the diagnosis of type 1 diabetes, OGTT will help to exclude the diagnosis of diabetes when the cause of hyperglycemia and/or glycosuria are atypical like an intercurrent illness, during steroid therapy, and in situations of renal glucosuria. When it is performed in children, the dose of oral glucose load to be given is 2 g/kg in children <3 years, 1.75 g/kg in 3–10-year-old and 75 g in children >10 years of age.^[21] First, after 8 h of overnight fasting blood glucose level is measured, and then 2 h after the above oral glucose load, blood glucose level is checked again. If the fasting blood glucose is above 126 mg/dl and/or 2 h blood glucose is above 200 mg/dl, the diagnosis of diabetes is made.^[22]

Modified OGTT could be performed to identify individuals with maturity-onset diabetes of the young (MODY), who may present as type 1 diabetes. In modified OGTT, in addition to blood glucose levels, insulin and C-peptide levels are measured in fasting, 30 min and 2 h after oral glucose load. In T1DM, there is only a mild or no increase in insulin and C-peptide levels. However, both in MODY and T2DM, variable and substantial insulin production could be seen in the presence of hyperglycemia.^[21] The C-peptide test is discussed in detail later.

The utility of HbA1c criteria in children is less well established compared to adults. According to a study from Germany, all new-onset T1DM children had an HbA1c value equal to or above 6.35%, whereas children with transient hyperglycemia had a value ranging from 4.5% to 6.1%.^[23] In Africa, and South Asia, atypical forms of DM in older children, adolescents, and young adults include ketosis-prone atypical DM, and Fibrocalculous Pancreatic Diabetes (FCPD).^[24] Ultrasound of abdomen showing calcifications with or without atrophic pancreas along with a history of recurrent abdominal pain with pancreatitis in a nonalcoholic thin built individual with new-onset diabetes will help to confirm the diagnosis of FCPD. FCPD is also called Type 3c diabetes.^[25]

Islet Autoantibodies

The breakthrough discoveries of islet cell antibodies (ICA) from a section of frozen pancreas by indirect immunofluorescence (1970) and ICA in the serum of people with T1DM (1974) ushered in the era of islet autoantibody testing. However, even though ICA are highly specific for beta-cell injury, they have many target molecules and therefore lack gold-standard diagnostic value. ICA have been largely abandoned because the indirect immunofluorescence assays are complex, labor intensive, and hard to standardize. Instead currently, the following islet autoantibodies namely glutamic acid decarboxylase 65 antibody (GADA), insulinoma-associated-2 autoantibody or islet tyrosine phosphatase autoantibody islet antigen-2 antibodies (IA-2A), zinc transporter 8 autoantibody (ZnT8A), and insulin autoantibodies (IAA) are being measured.

There are certain differences in the prevalence, presentation, and duration of antibody positivity in type 1 diabetes. Islet tyrosine phosphatase (IA 2), anti-GADA (Anti-GAD 65), and IAA are present in early T1DM but not in T2DM. IA 2 antibodies are present within 6 months from the diagnosis of T1DM and then begin to diminish. Even among the individuals with classical type 1 diabetes, in India, the prevalence of the usual islet cell-specific antibodies are significantly less than that reported among Western Caucasians.^[26] Anti-GAD antibody is present both at the time of diagnosis and persists longer.^[27] Checking for antibodies helps with confirming the diagnosis in more than 90% of individuals with elevated fasting blood glucose.

The primary investigation in T1DM involves the assessment of Anti-GAD 65. Glutamic acid decarboxylase (GAD) is an enzyme present in the beta cells of pancreas. The presence of anti-GAD 65 antibody has a sensitivity of 75% and specificity of 100% in type 1 diabetes diagnosis. As per a study conducted on subjects <25 years of age, it was shown that Anti-GAD 65 antibody value of >20.75 nmol/l and fasting C-peptide value <0.36 nmol/L (360 pmol/L) are a good indicator of autoimmune diabetes in children and young adults.^[28],[29]

If Anti-GAD 65 antibody is negative, then islet tyrosine phosphatase 2 (IA 2) and/or Zinc transporter 8 (ZNT8) tests should be ordered. Both Tyrosine phosphatase 2 (IA 2) and Zinc transporter 8 are pancreatic beta cell secretory granule membrane proteins which are identified as the target antigen for islet cell autoantibodies.^[30] Unlike type 1 A diabetes which is caused by the autoimmune destruction of beta cells of pancreas resulting in autoantibody positivity, idiopathic or type 1 B diabetes, even though there is absolute insulin deficiency, the cause of beta cell destruction is not known and autoantibodies are absent. Hence, the absence of antibodies does not rule out type 1 diabetes.^[31]

With respect to insulinoma-associated-2/tyrosine phosphatase IA-2As, two distinct constructs of the IA-2 were shown to account for two different immune reactivities in autoimmune diabetes. The intracytoplasmic IA-2 IC (605–979) construct showed the highest sensitivity when used to evaluate IA-2 immuno-reactivity in patients with newly diagnosed type 1 diabetes, whereas this construct was less frequent than the IA-2 fragment IA-2 (256–760) in patients with type 2 diabetes. Hence IA-2 IC (605–979) has a better diagnostic value in type 1 diabetes when compared to the other IA-2 construct.

It was demonstrated that in patients with type 2 diabetes, the prevalence of the type 1 diabetes-specific GAD, IA-2IC (605–979) autoantibodies significantly decreased as BMI increased.^[32] It was observed that, in islet autoantibody-positive patients, the frequency of IA-2 (256–760) significantly increased as BMI increased so that it became the most prevalent antibody in patients with BMI ≥30 kg/m². In addition, the presence of the IA-2 (256–760) A, when not associated with GADA, identified a phenotype resembling a classical obese patient with type 2 diabetes, with significantly higher BMI, waist circumference, total cholesterol, and uric acid level and a lower frequency of high-density lipoprotein cholesterol and TPO antibody positivity than patients positive for GADA alone. Taken together, these findings illustrate the clinical superiority of Anti-GAD 65 antibody when compared with IA 2 antibodies. LADA shows a slower progression to insulin requirement than patients with type 1 diabetes, but share a similar antibody pattern, albeit with significant quantitative differences. Anti-GAD 65 antibody is the ideal test for diagnosing LADA.

Zinc transporter-8 Autoantibody (ZnT8A), is another major biomarker for T1DM. Antibodies against ZnT8 are considered an independent demonstrator of autoimmunity for the diagnosis of T1DM. ZnT8 is a six-transmembrane protein transporter (member of cation diffusion family) which facilitates the transport of Zn²⁺ ions from the cytoplasm to insulin vesicles.^[33] It plays an essential role in the storage, secretion, structural stabilization, and action of insulin. Frequent exposure of ZnT8 antigen occurs during the exocytosis of insulin that is stimulated by glucose. ZnT8 exposure in genetically predisposed individuals can aggravate or activate the production of autoantibodies against ZnT8 antigens. According to Atkinson, et al. approximately 26% of T1DM subjects were found positive for ZnT8A, who were negative for antibodies against GAD, IA-2, and insulin antigen.^[34] In the Caucasian population, it has been reported that ZnT8A was discovered in more than 60% of individuals with type 1 diabetes, whereas, combined measurement of standard autoantibodies with ZnT8A increased the detection rates of type 1 diabetes to 98%.^[35] In an Indian study involving 88 subjects of age 2–18 years, with type 1 diabetes of less than 4-year duration, it was shown that 26% of T1DM subjects were positive for ZnT8A, who were negative for both GADA and IA2A. Combined use of ZnT8A and GADA could detect 97% of antibody-positive patients.^[36] Thus, the totality of evidence seems to suggest that ZnT8 antibody could be an important adjunct to anti-GAD 65 antibody. Given the high cost of ZnT8 antibody testing in India, it is better to perform a testing in Anti-GAD 65 negative subjects who have a compelling need for better diagnosis of type 1 diabetes.

The absence of standard autoantibodies in T1DM patients and the appearance of ZnT8A in the individuals before the disease development have led researchers to measure and associate these antibodies with a future risk of type 1 diabetes. In a study by Bhatty et al. done on a total of 50 subjects, with 25 cases being individuals with T1DM and the other 25 controls being the first-degree relatives of these cases with no autoimmune disease, it was shown that ZnT8A was significantly associated with T1DM. Controls with a positive family history of T1DM and ZnT8A values ≥9 ng/ml are at 10 times higher risk of developing T1DM.^[33] However, the role of ZnT8A in the prediction of type 1 diabetes is a topic of research, not clinical practice.

[Table 1], shows the sensitivity, specificity, and diagnostic cut-off for the islet autoantibodies of interest, according to a recent Indian study by Shivaprasad et al.^[36]

Table 1: Sensitivity, specificity, and diagnostic cutoff for the islet autoantibodies

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ICA is no longer recommended as this imprecise biological assay is superseded by the direct measure of single antibodies.^[37]

C-Peptide Levels

As the prohormone precursor pro-insulin is enzymatically cleaved into C-peptide and insulin in the beta cells of pancreas, the connecting peptide or C-peptide is produced in equal amounts to insulin. Hence, it is a good measure of endogenous insulin secretion in patients with diabetes. C-peptide has negligible clearance from the liver and constant peripheral clearance. Its half-life is about 20–30 min when compared to insulin which has a half-life of only 3–5 mins. With the rising incidence of T2DM in younger individuals, discovery of monogenic diabetes subtypes and therapies aimed at preserving insulin-secreting capacity, the importance of direct measure of insulin-secreting capacity has become more important both for the classification of diabetes and management of diabetes. The utility of C-peptide is greatest after 3–5 years of diagnosis of diabetes especially when these individuals still continue to maintain substantial insulin-secreting capacity pointing that the diagnosis is either T2DM or monogenic diabetes [Figure 1]. Absent C-peptide at any point of time indicates absolute insulin therapy requirement irrespective of the etiology and classification of diabetes. In other words, C-peptide levels are a direct indicator of the need for insulin therapy.

Figure 1: Flow chart for investigation of suspected type 1 diabetes in newly diagnosed adults.^[15] *Usually measurement units used to report C-peptide are: nmol/l, pmol/l and ng/ml. 1 nmol/l = 1000 pmol/l = 3 ng/ml. Adapted from Jones AG et al.^[39]

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The first radioimmunoassay for C-peptide was developed in 1970.^[38] The advent of highly sensitive and specific nonisotopic assays (chemiluminescence and immunofluorescence) utilizing monoclonal antibodies, has reduced the cost, which has improved detection limits and reproducibility. Despite these advances, some limitations still remain like optimal standardization of C-peptide measurements between different laboratories which are yet to be achieved. Additional barrier to the use of C-peptide measurement in clinical use is the nonavailability of reference ranges of specific population with diabetes.

Either fasting or stimulated (postprandial) C-peptide should be measured. The stimulated C-peptide is either done 90–120 mins after consumption of standardized mixed meal or as a formal poststimulation C-peptide measurement where in serum C-peptide is measured 6 min after intravenous injection of 1 mg of Glucagon in the fasting state.^[38] In type 1 diabetes, C-peptide is low. A stimulated C-peptide value of <0.6 ng/ml or <200 pmol/L indicates need for insulin therapy [Table 2].

Table 2: Suggested C-peptide thresholds to support clinical decisions in patients with insulin-treated diabetes

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Urine C-peptide is usually not measured as the value is not reliable when the kidney functions are not normal. C-peptide is excreted in the urine through the glomerular filtration and uptake from peri-tubular capillaries. The total quantity of C-peptide excreted in the urine per day represents about 5% of the pancreatic C-peptide secretion. Whereas the total quantity of insulin excreted in the urine is only 0.1% of the total insulin secreted by the pancreas. There appears to be inter/intraindividual variation in the fraction of C-peptide secreted in the urine and the C-peptide clearance also increases in individuals with diabetes due to hyperglycemia causing a high glomerular filtration rate. Due to these reasons and the practical difficulty of collecting 24 h urine, this test is not done usually. Spot urine C-peptide/creatinine ratio eliminates the problem with urine concentration variation and can replace the 24 h urine C-peptide test.^[38] It is important to note that the urine C-peptide/creatinine ratio may be 1.5 times higher in women than men, due to lower creatinine values in women.^[38],[39]

According to a recent consensus report by the ADA and the EASD published in September 2021, based on the data from the white European population, in adults with newly diagnosed suspected type 1 diabetes, the flow chart helps to clinch the diagnosis [Figure 1].^[15]

Genetic Testing

Molecular genetic testing is recommended for diabetes diagnosed before 6 months of age, irrespective of the current age, as more than 80% of them have monogenic neonatal diabetes. About 30%–50% of these individuals with monogenic diabetes have ATP-sensitive potassium (KATP) channel mutations and hence insulin can be replaced with sulfonylureas for management.^{[40],[41],[42]}

Differentiating Type 1 Diabetes from Monogenic Diabetes

Monogenic diabetes, also previously called MODY, is a rare autosomal dominant diabetes found in young individuals. It is found in 4% of those diagnosed with diabetes before the age of 30 years and the likelihood increases to 20%, if the islet cell auto-antibodies are negative and C-peptide secretion is maintained.

Monogenic diabetes should be considered when the following criteria are present: (a) diagnosis of diabetes <6 months of age, (b) a strong family history of diabetes is present without features of type 2 diabetes like obesity, (c) mild fasting hyperglycemia seen in young, nonobese children, (d) diabetes is present, but islet cell autoantibodies, obesity, and insulin resistance are absent, (e) unusual situations when the diagnosis of diabetes does not fit into classical type 1 or type 2 diabetes, and (f) clinical profile consistent with one of the known phenotypes of MODY mutations.

More than 60% of MODY is caused by the mutations in the genes Hepatocyte Nuclear Factor 1 Alpha (HNF1A) and Hepatocyte Nuclear Factor 4 Alpha. These subtypes of MODY respond well to sulphonylurea treatments and hence one is able to discontinue insulin therapy with improved glycemic control.^[43] Individuals with glucokinase (GCK) mutations do not require glucose-lowering therapies.^[44] Renal cyst and diabetes syndrome resulting from the mutation of hepatocyte nuclear factor-1 beta is a rare form of MODY. Patients with mitochondrial diabetes may develop severe insulin deficiency.^[45],[46]

As per the study by Mohan et al., HNF1A and ABCC8 are among the most frequently mutated MODY genes in south India.^[47],[48] Mutations in the KCNJ11 and ABCC8 genes, encoding the subunits of the (adenosine triphosphate sensitive potassium channel) KATP channel, most commonly manifest as neonatal diabetes, and can cause permanent or transient forms. Mutations in KCNJ11 and ABCC8 are also rare causes of MODY. Transient forms have a median onset of diabetes at 4 weeks and remit at a median age of 35 weeks, but may relapse later in life. Neurodevelopmental difficulties are a common feature of mutations in these genes. KATP-related neonatal diabetes can usually be treated with high doses of sulfonylureas, which also helps with the neurodevelopmental phenotype. Frequently people can achieve excellent diabetes control on sulfonylureas. More severe mutations and longer duration of misdiagnosis are associated with decreased success in transitioning from insulin therapy to sulfonylureas.^[49] Such patients with monogenic neonatal diabetes may develop absolute insulin deficiency in the absence of sulfonylurea treatment.^[50]

To date, there are about 20 different gene causes for neonatal diabetes. Out of these the commonest are the mutations in ABCC8 gene and KCNJ11 gene which encode the SUR1 and Kir6.2 subunits of the voltage-dependant potassium channel, respectively. Mutations in KCNJ11 and ABCC8 can cause transient neonatal diabetes, permanent neonatal diabetes, or developmental delay, epilepsy, and neonatal diabetes syndrome. Rarely insulin gene mutations can mimic type 1 diabetes, and this has been reported from India.^[51]

Differentiating Type 1 Diabetes Mellitus from Type 2 Diabetes Mellitus

In adults with newly diagnosed diabetes, diagnosis of T1DM may be challenging especially when the individuals have features of both type 1 and type 2, like older adult with normal or low BMI or young adult with elevated BMI. Ketoacidosis which once used to be a pathognomonic feature of type 1 diabetes, has also been reported in ketosis-prone type 2 diabetes individuals.^[15]

Misclassification of T1DM is common and about 40% of those developing type 1 diabetes are initially treated as having type 2 diabetes.^[52] No single clinical feature confirms type 1 diabetes in isolation. The most discriminative feature is younger age of onset, <35 along with lower BMI (<25 kg/m²). Features such as unintentional weight loss, ketoacidosis, and glucose value >360 mg/dl at presentation are also informative. Weak discriminators classically associated with type 1 diabetes include ketosis without acidosis, osmotic symptoms, and family history or history of autoimmune diseases.^[14],[53]

In a multi-center survey on patients <20years of age with new onset of diabetes in India, it was shown that T1DM is the most common subtype of diabetes in the young among Indians and that even though T2DM can occur in the young, it continues to be an uncommon entity.^[14] Also when compared to those with T2DM, individuals with T1DM were significantly younger at disease onset, had a lower BMI, higher prevalence of ketosis, lower C peptide levels, and were less likely to have a positive family history. On the other hand, individuals with T2DM had features suggestive of insulin resistance and dyslipidemia such as acanthosis nigricans, higher triglyceride values, and raised LDL. In another study on correlates of type 2 diabetes in children, adolescents, and young adults in North India, it was shown that when compared to the healthy controls, individuals with type 2 diabetes (mean age at diagnosis = 21 years of age) had three distinctive features namely, higher prevalence of hypertriglyceridemia, high waist–hip ratio, and a family history of diabetes.^{[14],[54],[55]}

Majority of older adults with low or normal BMI will have type 2 diabetes especially when the individual has ethnicity associated with a high risk of type 2 diabetes.^[56] Rapid progression to insulin therapy, usually in <3 years, is strongly suggestive of slow onset type 1 diabetes. The diagnosis becomes difficult when insulin therapy is started after slower progression. Controversy exists about Latent autoimmune diabetes of Adult (LADA) diagnosis, as to whether this is a discrete diagnosis or a subset of type 1 diabetes because the affected individuals have features of both type 1 and type 2 diabetes at varying degrees.^[57] LADA initially responds well to oral anti-diabetic medications like T2DM, but soon within 3 years, will require insulin therapy like TIDM. In a study from India, it was reported that a significant proportion, about one-fourth, of people with BMI <18.5 kg/m² and diabetes had LADA with anti-GAD 65 positivity.^[54]

Diagnosis in a Low Resource Setting

India is a developing country and hence most of the patients are not fortunate to have access to a comprehensive diabetes care facility urgently. In poor resource settings, especially in the rural area when children present with hyperglycemia and ketoacidosis, the primary goal is to achieve euglycemia with insulin therapy and hydration. When the patients fit the classic features of T1DM like diabetes in children or young adults who are thin-built and ketosis-prone in the absence of insulin, further workup is usually not done and the individual continues with the insulin therapy to maintain euglycemia and prevent complications. Further work up with C peptide and autoantibodies can be done after 3 months in individuals who do not fit the typical clinical picture of T1DM like patients requiring ≤ 0.5u/kg/day insulin requirement after 1 year of diabetes and individuals in a longer honeymoon period (more than a year). In such patients with atypical presentation when the diagnosis of T1DM is doubtful, further workup can be done by referring the patient to facilities where free health-care management including genetic testing is provided.

Patient Perspectives on Diagnosis

The diagnosis of type 1 diabetes is often sudden for families. Their lives change overnight, not only as a result of the new diagnosis of a physical condition but it also impacts the person with T1DM and the family, mentally, socially, and financially as well. T1DM is a chronic condition that places the burden of management largely on the individual living with it (or on the immediate caregivers/parents in the case of children and young people). Therefore, the correct diagnosis is essential.

Diabetes self-management, education, and support are essential and should be offered to people and families living with T1DM on a continuous basis, right from diagnosis. Insulin is the only line of management of T1DM. People with T1DM should be empowered to self-manage to maintain glycemic control while also being able to balance their quality of life. Basic diabetes education is crucial to success in both short-term and long-term T1DM management. People with diabetes and their caregivers should be able to work together comfortably as a team with their health care professionals towards a common goal of diabetes management. Treatment should be person-centered and acknowledge the impact and burden of diabetes on a person's life and should be dealt with respect and empathy.^{[58],[59],[60],[61]}

Peer support is also vital in the management of diabetes since it brings together collective knowledge, wisdom, and real-life experiences and insights. Such support systems help overcome barriers of stigma, dealing with fears, and learning from one another.

Summary

T1DM accounts for about 5%–10% of all cases of diabetes. The incidence is increasing at the rate of about 3%–5%/year. A recent study found an incidence of 4.9 cases/100,000/year in India. However globally there is a significant rise (by 9.5%) in the incidence of type 1 diabetes in the pediatric age group in the covid pandemic time in 2020 when compared to pre-covid times. Youth onset diabetes in the age group of 20–40, is generally associated with misclassification. In this age group, type 1 diabetes needs to be differentiated from type 2 diabetes and maturity onset diabetes of young [Table 3].^[2] However, in younger age group type 1 diabetes need to be differentiated from neonatal diabetes, mitochondrial disease, and FCPD. Diabetes resulting from endocrinopathies, disease of exocrine pancreas, infection, and drugs should also be in the differential diagnosis, during the evaluation of new-onset diabetes. Timely diagnosis and appropriate management are crucial to prevent complications and provide good quality of life for Type 1 DM individuals.

Table 3: Differential diagnosis between youth onset type 1 diabetes mellitus, type 2 diabetes mellitus and maturity onset diabetes of the young

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Nil.

Conflicts of interest

There are no conflicts of interest.

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